Narcoleptic patients experience cataplexy, which is a sudden loss of muscle tone most commonly in response to the sudden onset of strong emotions, excessive daytime sleepiness and fragmentation of sleep during the night. Current drug treatments can be dichotomized into those that are aimed at daytime sleepiness, typically using dopamine agonists or psychostimulants, and those that are aimed at cataplexy, typically using tricyclic antidepressants. Drug side effects, residual sleepiness and cataplexy episodes continue to be major problems for most treated narcoleptics (Aldrich, M. S., 1998, Neurology 50: S2–S7).
It has been reported that narcolepsy is linked to dysfunction of the newly discovered hypocretin (Hcrt) (orexin) peptide system. This report was based on a deletion in the transcripts of the hypocretin receptor 2 (Hcrt-2) gene in narcoleptic Dobermans and Labradors (Lin, L. et. al., Cell (1999) 97: 365–376). A mutation in the gene responsible for the hypocretin-2 (Orexin-2) receptor was reported to be a genetic cause of canine narcolepsy (Lin, L. et al., 1999, Cell 98: 365–376). A null mutation of the gene encoding the two known hypocretin (Hcrt) peptides produces aspects of the narcolepsy syndrome in mice (Chemelli, R. M. et al., 1999, Cell 98: 437–451). Human narcoleptics have reduced levels of Hcrt-1 in their cerebrospinal fluid (Nishino, S. et al., 2000, The Lancet 355: 39–40).
Basic research on the behavioral effects of the hypocretins has generally used intracerebroventricular or intra-parenchymal microinjection of the peptide (Hagan, J. J. et al., 1999, Proc Natl Acad Sci U.S.A. 96: 10911–10916; Dube M. G., et al., Brain Res. 842: 473–477). The results in this area are controversial. Some studies have concluded that Hcrts administered systemically do not cross the blood-brain barrier (BBB) at sufficient levels to affect physiological function (Chen, C-T et al., 1999, Soc Neurosci Abst 25: 12; Takahashi, N. et al., 1999, Biochem Biophys Res Commun 254: 623–627), making development of an Hcrt receptor agonist with good BBB permeability a high priority. One group reported that iodinated Hcrt-1 passes the BBB (Kastin, A. J. and Akerstrom, V., 1999, J Pharmacol Exp Ther 289: 219–223.) but iodination is known to increase BBB permeability. This result does not remove the question whether the native peptide will pass the BBB.